HCV poly U/UC sequence-induced inflammation leads to metabolic disorders in vulvar lichen sclerosis.

Vulvar lichen sclerosis (VLS) is a dermatologic disorder that affects women worldwide. Women with VLS have white, atrophic papules on the vulva. They suffer from life-long intense pruritus. Corticosteroids are the first-line of treatments and the most effective medicines for VLS. Although VLS has been speculated as an autoimmune disease for a long time, its pathogenesis and the molecular mechanism is largely unknown. We performed a comprehensive multi-omics analysis of paired samples from VLS patients as well as healthy donors. From the RNA-seq analysis, we found that VLS is correlated to abnormal antivirus response because of the presence of Hepatitis C Virus poly U/UC sequences. Lipidomic and metabolomic analysis revealed that inflammation-induced metabolic disorders of fatty acids and glutathione were likely the reasons for pruritus, atrophy, and pigment loss in the vulva. Thus, the present study provides an initial interpretation of the pathogenesis and molecular mechanism of VLS and suggests that metabolic disorders that affect the vulva may serve as therapeutic targets for VLS.

Novel Therapeutic Approaches and Targets for Treatment of Vulvar Lichen Sclerosus.

BACKGROUND: Vulvar Lichen Sclerosus (VLS) is a chronic inflammatory disease with a huge impact on a person's quality of life. A correct therapy is required for relieving symptoms, reversing signs and preventing further anatomical changes. OBJECTIVE: The main objective of the present paper is to provide suggestions for the best treatment approach, based on the available evidence. Treatment strategies are divided on the basis of the treatment phase, distinguishing options for initial, acute or attack treatment and those for long-term, maintenance treatment. METHODS: An electronic search was performed using the National Library of Medicine PubMed database. All the studies evaluating treatment of vulvar lichen sclerosus published in the English literature were analyzed, including controlled studies, case series, guidelines and reviews. RESULTS: Current evidence identifies ultra-potent and potent corticosteroids, administered for 12 weeks, as the first-line recommended treatment for active VLS. Topical calcineurin inhibitors, tacrolimus and pimecrolimus, are effective and safe alternatives. Long-term maintenance strategies aimed at preventing recurrences are required, after the initial treatment phase. Maintenance treatment mostly consists in topical corticosteroids, administered i) on an "as needed" basis ("reactive" scheme), ii) on a continuative regimen, iii) on a low-dose, intermittent regimen ("proactive" scheme). Further investigations are needed for better defining the placement of other options within the VLS therapeutic algorithm, including retinoids, physical and systemic treatments. CONCLUSION: The available evidence provides useful indications for the management of VLS. Both the identification of new therapeutic targets and the optimization of the available options represent the main objectives of future research.

Structured analysis of histopathological characteristics of vulvar lichen sclerosus in a juvenile population.

Genital lichen sclerosus (LS), a chronic noninfectious dermatosis, is not rare in pediatric dermatology. The histopathological diagnosis in children and adults in both genital and nongenital LS is considered to be the same and encompasses a broad range of possible characteristics. Clinical manifestations and treatment options of genital LS in children are different depending on gender. The vast majority of boys are treated with circumcision, making for a larger amount of information on the histopathology of genital LS in boys, whereas substantial information on the histopathology of juvenile vulvar LS is lacking. In girls, vulvar LS almost always persists beyond puberty and, therefore, presents a particular challenge to clinicians and cause for concern for the patient. Vulvar LS in childhood and adolescence (juveniles) is underreported, and there are uncertainties with regard to the long-term course of the disease when it occurs at an age when the vulva is still developing. The present study investigates biopsies of 100 juvenile cases of vulvar LS and analyzes the presence or absence of the most salient histopathological characteristics of LS that are described in the literature. We found that the range of histopathological characteristics known for adult LS are also present in juvenile vulvar LS, even at very young ages, including histopathological features associated with autoimmune disease, in support of the idea of a similar pathogenesis.

An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155.

Vulvar lichen sclerosus and lichen planus are T-cell-mediated chronic skin disorders. Although autoimmunity has been suggested, the exact pathogenesis of these disorders is still unknown. Therefore, the aim of the current study was to investigate the molecular and immunological mechanisms critical to the pathogenesis of vulvar lichen sclerosus and lichen planus. By using gene expression profiling and real-time RT-PCR experiments, we demonstrated a significantly increased expression of the pro-inflammatory cytokines (IFNγ, CXCR3, CXCL9, CXCL10, CXCL11, CCR5, CCL4, and CCL5) specific for a Th1 IFNγ-induced immune response. In addition, BIC/microRNA-155 (miR-155)--a microRNA involved in regulation of the immune response--was significantly upregulated in lichen sclerosus and lichen planus (9.5- and 17.7-fold change, respectively). Immunohistochemistry showed a significant T-cell response, with pronounced dermal infiltrates of CD4(+), CD8(+), and FOXP3(+) cells. In conclusion, these data demonstrate an autoimmune phenotype in vulvar lichen sclerosus and lichen planus, characterized by increased levels of Th1-specific cytokines, a dense T-cell infiltrate, and enhanced BIC/miR-155 expression.

Lichen sclerosus: a review of literature and a case of an atypic surgical treatment.

Lichen sclerosus is a chronic immuno-mediated skin disease of the genital region in men and women. The treatment may be pharmacological or surgical, the choice depending on the extension of the involved area, the histological pattern and the level of functional disease complained by the patient. If the biopsy is negative for neoplastic degeneration the treatment may be pharmacological only. In our paper, we describe the case of a patient with vulvar disease and labial fusion, burial of the clitoris and severe introital stenosis. In this case, the treatment was surgical.

Vulval lichen sclerosus and lichen planus.

Lichen sclerosus (LS) and lichen planus (LP) are both immunologically mediated diseases with a preference for the genitalia. The basic principles of management of vulval LS and vulvovaginal LP are the same and involve explanation of the disease, emphasizing the chronic nature of the condition and outlining treatment options. The main difference between the two conditions is that LP has a propensity to involve the mucous membranes including the mouth and vagina which are rarely affected in LS. First-line treatment for LS is a super-potent topical corticosteroid ointment which has a high response rate. Erosive vulvovaginal LP is more challenging to treat. Second-line therapies include topical calcineurin inhibitors and systemic agents. There is limited evidence for systemic treatments for both conditions. The risk of vulval squamous cell carcinoma (SCC) is increased in both LP and LS, and it is not known how treatment affects this risk. We recommend teaching self-examination and longitudinal evaluation.

Childhood vulval lichen sclerosus: autoimmunity to the basement membrane zone protein BP180 and its relationship to autoimmunity.

Lichen sclerosus (LS) is associated with autoimmune disease in female children and adults. In adult women, there are antibody and T-cell responses to proteins in the basement membrane zone (BMZ). The aim of this study was to investigate reactivity to the BMZ in girls with LS. Nine girls with vulval LS were studied clinically and serologically. The presence of circulating BMZ autoantibodies was investigated. Autoimmunity was assessed by personal and family history of autoimmune diseases and autoantibodies. We detected circulating BMZ antibodies in four of the nine children, all with IgG responses. Three patients were positive by indirect immunofluorescence, one had a positive ELISA reaction to bullous pemphigoid antigen (BP)180, and three had a positive reaction on BP180 immunoblots. There was no association with autoimmune disease or clinical features. To our knowledge, this is the first study to find BMZ autoantibodies in children with vulval LS. The autoantibodies were directed at BP180 and were exclusively of the IgG class.

The effect of topical pimecrolimus on inflammatory infiltrate in vulvar lichen sclerosus.

OBJECTIVE: Lichen sclerosus (LS) is a relatively common chronic inflammatory disorder of the skin and mucosal surfaces. STUDY DESIGN: A total of 29 women with histologically confirmed, active LS were recruited to this study with 2 aims. First, we evaluated the effectiveness of pimecrolimus treatment to LS not responding to conventional corticosteroid treatment. The second aim in this study was to provide information of in vivo effects of topical pimecrolimus in acute LS lesions, especially the inflammatory cell infiltration. RESULTS: In all, 25 of 29 women applied cream as recommended. After 2 months of treatment, 20 patients had reached partial or complete clinical remission. Histology showed decreased inflammatory lymphoid infiltrate with down-regulation of CD3(+) T cells, CD8(+) T cells, and CD57(+) natural killer cells. Also macrophage marker CD68 staining showed down-regulation. There was no change in CD20(+) B lymphocytes. CONCLUSION: We conclude that calcineurin inhibitors are an effective treatment for patients not responding to corticosteroid treatment.

T cells reactive with the NC16A domain of BP180 are present in vulval lichen sclerosus and lichen planus.

BACKGROUND: Lichen sclerosus (LS) is a chronic inflammatory skin condition. The recent demonstration of circulating autoantibodies to extracellular matrix protein 1 and to basement membrane zone (BMZ) components, chiefly BP180, suggests that autoimmunity to these components might contribute to pathogenesis. However, there is no binding of autoantibodies in vivo and as LS is characterized by a lymphocytic infiltrate, it seems likely that LS is mediated, in part, by antigen-specific lymphocytes. Similar mechanisms may apply to vulval lichen planus (LP), an interface dermatitis, with clinical and immunological overlap with LS. OBJECTIVES: This study aims to test the hypothesis that T cells reactive with the NC16A domain of BP180 are present in the peripheral blood of patients with vulval LS and LP. METHODS: Isolated peripheral blood mononuclear cells from 14 patients with vulval LS, 5 with vulval LP and 4 healthy controls were grown in vitro. We examined for immunogenicity of overlapping peptides spanning the NC16A domain of BP180 using interferon-gamma enzyme-linked immunospot assay (ELIspot) on the cultured T-cell lines. BMZ antibodies were assayed, HLA type determined and clinical parameters noted. RESULTS: Significant interferon-gamma production was observed in response to the NC16A peptides in 6 of the 14 vulval LS and 2 of the 5 LP patients, but not in the control subjects. There was an associated autoantibody response to BP180 in 3 LS and 1 LP patient with T-cell responses. These data suggest that in some vulval LS and LP patients, NC16A domain-specific T cells circulate at sufficiently high frequency to be detectable in vitro and show rapid effector function. There was no association with HLA type or clinical parameters. CONCLUSION: We have demonstrated that in > 40% of our vulval LS and LP patients, the NC16A domain of BP180 is a target for circulating T cells, and in vulval LS and LP there are associated autoantibodies to BP180.

Chlamydia trachomatis infection in women with lichen sclerosus vulvae and vulvar cancer.

OBJECTIVE: Chronic infections in the urogenital area often precede or coexist with vulvar cancer. A strong connection between some tumours and the-appearance of Chlamydia trachomatis infection has been observed, but there is little information concerning a connection of that infection with vulvar cancer and lichen sclerosus vulvae (LS). The aim of this study was the analysis of frequency of antigens appearance and antibodies of IgM and IgG Chlamydia trachomatis in patients with vulvar cancer and LS and we wanted to find the correlation between Chlamydia trachomatis infection and vulvar cancer and LS. METHODS: 80 women treated in the Clinic of Vulva Diseases at the Department and Clinical Ward of Gynaecology, Obstetrics and Oncological Gynaecology in Bytom, in the Silesian Medical University in Katowice were divided into two groups - 30 were treated for vulvar cancer and 50 were treated because of LS. We took bacterial smears vagina and cervical smears for presence of Chlamydia trachomatis antigens and peripheral blood to mark antibodies of IgM and IgG Chlamydia trachomastis. RESULTS: Chlamydia trachomatis antigen was found in 20% women with vulvar cancer and in 12% women with LS (p>0.05). In 13,3% cases with vulvar cancer we observed IgM Chlamydia trachomatis antibodies. In the group with LS IgM antibodies appeared in 16% women (p>0.05). In 50% patients with vulvar cancer in blood serum we observed IgG Chlamydia trachomatis antibodies, and in 16% women with LS (p<0.001). CONCLUSIONS: Previous Chlamydia trachomatis infection can lead to vulvar carcinogenesis.

The association of lichen sclerosus and erosive lichen planus of the vulva with autoimmune disease: a case-control study.

OBJECTIVE: To investigate the prevalence of autoimmune disease and circulating autoantibodies in women with lichen sclerosus (LS) and erosive lichen planus (LP) of the vulva and to compare these with a control population. DESIGN: Age- and sex-matched controlled study. SETTING: The vulval clinics in Oxfordshire, England, for patients with LS and LP. Healthy controls were recruited from the hospital and community. PATIENTS: A total of 190 women with the typical features of adult-onset LS of the vulva, 126 women with adult-onset erosive LP of the vulva, and 922 female controls (of whom 230 were examined). INTERVENTIONS: Personal history of autoimmune disorder for patients and controls, family history of autoimmune disorder for vulval LS and LP cohorts, and an autoantibody screen. MAIN OUTCOME MEASURES: The presence or absence of a personal or family history of autoimmune disorder, and the presence or absence of 1 or more circulating autoantibodies. RESULTS: The mean ages of patients with LS, patients with erosive LP, and control patients were 63, 61, and 61 years, respectively. The mean age of the 230 controls examined (including those who had serum autoantibodies assayed) was 62 years. Autoimmune disorders were more frequent in patients with erosive LP compared with controls (29% vs 9%; P < .001) and in those with LS compared with controls (28% vs 9%; P < .001). Circulating autoantibodies were more frequent in those with erosive LP compared with controls (41% vs 20%; P < .001). Conclusion This study demonstrates an association of autoimmune disorder and autoantibodies with erosive LP of the vulva and confirms the autoimmune associations of vulval LS.

Langerhans cells in vulvar lichen sclerosus and vulvar squamous cell carcinoma.

INTRODUCTION: Langerhans cells (LCs), specializing in antigen presentation, are a very important part of the skin immune system (SIS). MATERIALS AND METHODS: Skin biopsies from 22 women with vulvar lichen sclerosus (LS): 15 patients with early and 7 with the late stage of the disease, were evaluated. Five women with vulvar squamous cell carcinoma (SCC) were also examined. The control group consisted of 9 women who underwent plastic surgery of the vulvar region. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissues samples using antihuman CD1a antibody (NCL-CD1a-235, Novocastra). RESULTS: Increased numbers of LC stainings were present in early LS, whereas decreased numbers of these cells were present in late LS and in SCC compared with the control group. CONCLUSIONS: This study showed that dysregulation of the SIS may lead to suppression of LCs in the vulvar epithelium and may be one of the reasons for a higher tendency for carcinogenesis in the vulvar region.

Cytokine alterations in lichen sclerosus: an immunohistochemical study.

BACKGROUND: Although the histology of lichen sclerosus is characteristic, the precise nature of the inflammatory changes and the signals provoking them is uncertain. OBJECTIVES: To delineate the inflammatory changes in lichen sclerosus more accurately by studying cytokine changes. METHODS: An immunohistochemical study of 12 specimens of genital lichen sclerosus and one specimen of extragenital lichen sclerosus was undertaken using monoclonal antibodies to interferon (IFN)-gamma, IFN-gamma receptor, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-2 receptor (CD25), intercellular adhesion molecule-1 (ICAM-1) and its ligand CD11a. Control specimens were seven specimens of normal vulva obtained during gynaecological procedures, three specimens of normal skin, adjacent uninvolved thigh from three of the patients with lichen sclerosus, five specimens of nonvulval psoriasis, four specimens of nonvulval lichen planus and two specimens from chronic wounds. RESULTS: The lichen sclerosus specimens demonstrated slightly increased staining for IFN-gamma within the epidermis compared with the normal vulva and nonvulval skin. There was increased dermal staining for IFN-gamma both within the pale zone of the upper dermis and within the inflammatory zone below this. We confirmed our previous demonstration that in lichen sclerosus HLA-DR immunostaining is increased in association with vascular endothelium, the inflammatory cell infiltrate and around the keratinocytes. The areas of the epidermis with the strongest immunostaining for HLA-DR generally also had the strongest staining for IFN-gamma. In the lichen sclerosus specimens the zone of inflammation also demonstrated increased immunostaining for TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 while the zone of sclerosus demonstrated a smaller increase in immunostaining for IFN-gamma receptor, TNF-alpha, CD11a and ICAM-1, and the epidermis demonstrated increased staining for ICAM-1. CONCLUSIONS: The increased staining for IFN-gamma, TNF-alpha, IL-1alpha, IFN-gamma receptor, CD25, CD11a and ICAM-1 suggest that the cytokine response in lichen sclerosus shares characteristics of the cytokine response in lichen planus and chronic wounds.

Fetal microchimerism is not involved in the pathogenesis of lichen sclerosus of the vulva.

OBJECTIVES: The aim of this study was to investigate a possible relationship between fetal cell microchimerism and lichen sclerosus of the vulva. We searched for the presence of male cells and DNA in vulval tissue samples. METHODS: Paraffin-embedded skin biopsy samples from 15 women affected with vulval lichen sclerosus who gave birth to at least one son were analyzed for the presence of microchimeric male cells using fluorescence in situ hybridization (FISH) and fluorescent PCR. We included three lichen sclerosus samples originating from women without male offspring, six vulval specimens without pathological finding originating from autopsies and seven male gingival specimens as controls. RESULTS: Nucleated cells containing Y-chromosome specific sequences were neither detected at any site of the lesions nor in normal vulval specimens by using FISH. These results were confirmed by the use of PCR amplification demonstrating only DNA sequences specific for the X chromosome. No female microchimerism was detected in the male gingival samples. CONCLUSION: Despite the limited number and size of the samples, we conclude that persistent male fetal cells are not involved in the pathogenesis of lichen sclerosus of the vulva, since we consistently could not detect Y-chromosome specific sequences by using two molecular techniques.

The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus, and HLA DRB10301/04 and its associated DRB10301/04/DQB10201/02/03 haplotype protects from vulval lichen sclerosus.

Lichen sclerosus (LS) is considered to have an immunogenetic background. Several small studies, using serological typing, have reported that HLA-DR11, DR12, and DQ7 were increased in LS, with DR17 less frequent. This study aimed to validate and detect new HLA-DR and DQ associations with LS in females and its characteristic clinical parameters. The cases, 187 female LS patients, and 354 healthy controls were all UK North Europeans. PCR-sequence specific primers method was applied to genotype the HLA-DR, DQ polymorphisms that correspond to 17 serologically defined DR and seven DQ antigens. Statistical analysis was performed with two-tailed Fisher's exact test with Bonferroni adjustment (p value after Bonferrroni adjustment, Pc). We found increased frequency of DRB1*12 (DR12) (11.2%vs 2.5%, pc < 0.01) and the haplotype DRB1*12/DQB1*0301/04/09/010 (11.2%vs 2.5%, p < 0.001, pc < 0.05), and a lower frequency of DRB1*0301/04 (DR17) (11.8%vs 25.8%, pc < 0.01) and the haplotype DRB1*03/DQB1*02DRB1*0301/DQB1*0201/02/03 (11.2%vs 24.6%, pc < 0.0001) in patients compared with controls. HLA DR and DQ antigens were not associated with time of onset of disease, site of involvement, structural changes of genitals, and response to treatment with potent topical steroids. In conclusion, HLA-DR and DQ antigens or their haplotypes appear to be involved in both susceptibility to and protection from LS.